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Challenges for orphan medicines entering the European market – Part 2: Clinical evidence development

By 04/02/2021 2 Comments
4 roadblocks facing orphan medicines seeking to achieve market access in Europe - Part 2 Clinical evidence development. From Mtech Access

In this four-part series, we explore the various challenges facing orphan medicines entering the European market and suggest solutions that can help improve patient access. In Part 2 of the series, we explore challenges linked to clinical evidence development. You can find Part 1 here, exploring disease knowledge and awareness.

Clinical evidence generation is a crucial stage in the market access journey for all new treatments, but can be a more significant hurdle for orphan medicines.

The characteristics of rare diseases make meeting payer evidence requirements difficult. When a non-rare disease treatment enters the market, a payer is typically presented with high quality evidence from the manufacturer, including extensive Phase 3 clinical trial data for the new treatment and comparisons with other currently available interventions. This depth of evidence is often unavailable for rare diseases.

Challenges in generating clinical evidence

Orphan drug manufacturers frequently face the following challenges when generating clinical evidence:

  • Due to the small target population and the severity of most rare diseases, trial design and enrolment is challenging and far from the ideal double-blinded, comparative, parallel design of gold-standard randomised clinical trials. My colleague, Shona Lang, recently explored this and other related challenges in her article How clinical judgement can strengthen evidence-based medicine’.
  • Due to the rarity and chronic nature of many of these diseases, it is often difficult to demonstrate a statistically significant impact on a mortality outcome within a randomised trial duration; thus, trials may rely on biomarkers and surrogate endpoints. This adds uncertainty to payers around the clinical evidence, for whom impact on hard endpoints is key.
  • Rare disease indications are often heterogeneous and patients enrolled in trials may have associated co-morbidities, which, coupled with small patient numbers, further contribute to evidence generation challenges. Whilst this suboptimal level of clinical evidence is acknowledged and addressed at the regulatory level, guidance is scarce or non-existent at national and subnational payer level.1
  • On top of these challenges, manufacturers looking to develop an orphan medicine often need to address the requirements for paediatric medicines at an early stage for regulatory approval, given that many rare diseases affect children.2

It should be noted that countries are adapting their reimbursement processes to recognise these differences. A recent study found that 13/32 European countries use supplemental appraisal/reimbursement processes for orphan medicines.3 These allow application of different evidence requirements and thresholds (e.g. higher incremental cost-effectiveness ratio thresholds may be accepted by NICE when products are assessed via the Highly Specialised Technologies route) or may lead to exemption from the HTA process in some markets (e.g. Germany) if certain criteria are met. Therefore, manufacturers need to map and navigate these different processes.

On the other hand, where specific processes do not exist for orphan medicines, manufacturers need to understand how the general processes and requirements may challenge successful reimbursement in those countries.

Solutions to improve clinical evidence generation for rare diseases

To improve opportunities for broad and timely access of orphan medicines, manufacturers need to minimise the high level of uncertainty in their clinical data. This may be achieved by:

  • Identifying biomarkers and start/stop criteria to better define the patient population and treatment duration.
  • Applying and/or developing disease-specific patient-reported outcomes and health-related quality of life tools.
  • Identifying surrogate endpoints with proven clinical utility.
  • Designing and implementing post-launch evidence development plans and capturing real world data.

With all these approaches, manufacturers must consider the view of all stakeholders, including regulators, payers, clinicians, and patient advocacy organisations.

4 roadblocks facing orphan medicines seeking to achieve market access in Europe: 1) disease knowledge and awareness, 2) Clinical evidence development, 3) Economic evidence development, 4) Operational challenges

This series explores the challenges facing orphan medicines seeking to achieve market access in Europe. In this article we address the second roadblock – clinical evidence development.

If you’d like to discuss these topics with us and would like to hear more about how we can help you overcome your current challenges in a rare disease area, please email info@mtechaccess.co.uk to arrange a meeting with one of our experts.


  1. European Medicines Agency. Guideline on Clinical Trials in Small Populations. 2006. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-trials-small-populations_en.pdf. Accessed on: January 2021
  2. European Medicines Agency. Paediatric Regulation. 2017. Available from: https://www.ema.europa.eu/en/human-regulatory/overview/paediatric-medicines/paediatric-regulation. Accessed on: January 2021
  3. Nicod E, Whittal A, Drummond M, Facey K. Are supplemental appraisal/reimbursement processes needed for rare disease treatments? An international comparison of country approaches. Orphanet Journal of Rare Diseases. 2020;15(189):50. https://doi.org/10.1186/s13023-020-01462-0

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